Orthotamine benzoylpyridine and medicinal products based on them

 

(57) Abstract:

The invention relates to new orthotamine benzoylpyridine formula (1), where R(1) - H, alkyl with 1-8 C-atoms, Xand-(CH2)b-(CF2)c-CF3where a, b, C = 0; one of the two substituents R(2) and R(3) means-O-CO-R(27), respectively, and the other substituents R(2) and R(3) is R(1) where R(27) - alkyl with 1-8 C-atoms; R(4) is hydrogen, alkoxy with 1-4 C-atoms, F, Cl, Br, I; R(5) is hydrogen, and their pharmaceutically acceptable salts. Drug, possess inhibitory activity against Na+/H+-contains a compound of formula 1 and target additional additives. The compounds of formula 1 are used to receive medication for the treatment or prevention caused by ischemic conditions, diseases, heart attacks, strokes, etc. the Technical result is to provide new compounds having inhibitory activity against Na+/H+exchange. 2 C. and 15 C.p. f-crystals.

The invention relates to benzoylpyridine formula I

< / BR>
where mean:

R(1) - H, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms or Xa-(CH2)b-(CF2)c-CF3where a, b, C=0, one of the two substituents R(2) and R(3) OSN edelen as R(1);

R(4) means hydrogen, alkoxy with 1, 2, 3 or 4 C-atoms, F, Cl, Br, I; R(5) means hydrogen, and their pharmaceutically tolerable salts.

Preferred orthotamine benzoylpyridine formula I, where mean:

R(1) - H, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms or Xa-(CF2)c-CF3where a, C=0, one of the two substituents R(2) and R(3) means-O-CO-R(27);

R(27) alkyl with 1, 2, 3 or 4 C-atoms, and the other of the substituents R(2) or R(3) is defined as R(1);

R(4) means hydrogen, alkoxy with 1 or 2 C-atoms, F, Cl, and R(5) means hydrogen, and their pharmaceutically tolerated salts.

Especially preferred are the compounds of formula I, where mean:

R(1) - H, alkyl with 1, 2, 3 or 4 C-atoms or Xa-CF3where a=0, one of the two substituents R(2) and R(3) means-O-CO-R(27);

R(27) alkyl with 1, 2, 3 or 4 C-atoms, and the other of the substituents R(2) or R(3) is defined as R(1);

R(4) means methoxy, F, Cl, and R(5) means hydrogen, and their pharmaceutically tolerated salts.

Especially preferred orthotamine benzoylpyridine formula I, where mean:

R(1) - H, alkyl with 1, 2, 3 or 4 C-atoms or CF3one of the two substituents R(2) and R(3) means-O-CO -, WITH THE F, Cl;

R(5) means hydrogen, and their pharmaceutically tolerated salts.

These alkyl residues can be straight or branched chain.

The compounds of formula I according to the invention can be obtained by the method lies in the fact that the compound of formula II

< / BR>
where R(1)-R(5) have the above values, and L denotes easily nucleophile replaced the deleted group, is subjected to the interaction with guanidine.

Activated derivatives of the acid of formula II, where L denotes an alkoxy, preferably a methoxy group, fenoxaprop, phenylthio-, methylthio-, 2-pyridylthio, nitrogen heterocycle, preferably 1-imidazolyl, preferably get a known manner from the acid chlorides of carboxylic acids (formula II, L = Cl), which, in turn, can also be obtained in a known manner from the corresponding carboxylic acids (formula II, L=OH), for example, chloride tiomila.

Along with anhydrides of carboxylic acids of the formula II (L=Cl) can be obtained also other activated acid derivatives of the formula II in a known manner directly from the underlying derivatives of benzoic acid (formula II, L= OH) as the methyl ester of the formula II with L=cos what imazalil, Staab, Angew. Chem. English edition 1, 351-367 (1962)], the mixed anhydrides II with Cl-COOC2H5or chloride tosilos in the presence of triethylamine in an inert solvent, as activation of benzoic acids with dicyclohexylcarbodiimide (BCA) or with O-[(cyano(etoxycarbonyl)methylene)amino] -1,1,3,3-tetramethylurea-tetrafluoroborate ("TOTU") (Proceedings of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991). A number of suitable methods for obtaining activated derivatives of carboxylic acids of formula II are listed in the literature in J. March, Advanced Organic Chemistry, issue 3 (John Wiley & Sons, 1985), page 350.

The interaction of activated carboxylic acid derivatives of the formula II with guanidine carried out in a known manner in proton or aprotic, but inert organic solvent. In this case the interaction of the methyl esters of benzoic acids (II, L=OMe) with guanidine was suitable methanol, isopropanol or tetrahydrofuran with a temperature of 20oC to the boiling point of these solvents. Most interactions of compounds II with salt-free guanidine was advantageous to work in an aprotic inert solvents, such as tetrahydrofuran, dimethoxyethane, dioxane. But in the interaction of soedineniya.

If L denotes CL, it is advantageous to work with the addition of traps acid, for example, in the form of excess guanidine, to bind halomonadaceae acid.

Part of the underlying derivatives of benzoic acid of the formula II are known and described in the literature. Unknown compounds of formula II can be obtained well-known from the literature methods. Received benzoic acid according to any of the above options how to make the compounds according to the invention I.

The introduction of certain substituents in the 2-, 3-, 4 - and 5-position are able to make known from the literature methods using palladium reaction cross combinations of aryl halides or aritifical, for example, organostannic, organoboronic acids or organoboranes or copper organic or tsinkorganicheskih connections.

Benzoylpyridine are, in General, weak bases and can bind the acid with the formation of salts. As the acid additive salts take into account salts of all pharmacologically tolerated acids, for example, the halides, especially hydrochloride, lactates, sulfates, citrates, tartratami, acetates, phosphates, methylsulfonate, p-toluensulfonate.

Connections on the patent 612723 AND 1 (NOAH 93/F 054). They contain a hydroxyl group as substituents in the phenyl nucleus, but do not contain substituents in ortho-position.

In contrast to the known compounds, the compounds according to the invention distinguish themselves by a high efficiency in the inhibition of Na+/N+- sharing, and improved solubility.

They are not as well-known connection of any unwanted and negative solidarities properties, however, have a good antiarrhythmic properties, as for example, they are important for the treatment of diseases that appear with symptoms of lack of oxygen. Connection due to their pharmacological properties suitable as antiarrhythmic drugs with cardiotoxin component for the prophylaxis and treatment of infarction and for the treatment of angina, and they are also helpful inhibit or greatly reduce the pathophysiological processes in the occurrence of ischemia-induced damage, especially during provoking ischemia-induced arrhythmias of the heart. Because of their protective actions against pathological hypoxic and ischemic situations, the compounds according to the invention of formula I, as indicated in the of edst for the treatment of all acute or chronic, ischemia-induced damage or caused as a result of this primary or secondary disease. This applies to their use as pharmaceuticals for surgical interventions, for example, transplant organs, and connections can be used to protect the organs in the donor before the procedure and during the seizure, taken to protect organs, for example, in the treatment or during storage in physiological solutions, and during the transfer to the recipient's organism. The compounds are also valuable medicines with protective action when conducting angioplasticheskih surgical interventions, for example on the heart and peripheral vessels. In accordance with their protective effect against ischemia-induced damage, the compounds are suitable as pharmaceuticals for the treatment of ischemia of the nervous system, especially the Central nervous system, and they are suitable, for example, for the treatment of stroke or of cerebral oedema. In addition, the compounds according to the invention of formula I are also suitable for the treatment of various forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

On the other hand, the compounds according to the invention fo, is roliferation cells and cell proliferation of the smooth muscle tissue of blood vessels. Therefore, the compounds of formula I used as a valuable therapeutic agent for the treatment of diseases in which cell proliferation represents a primary or secondary cause, and can therefore be used as antiatherosclerotic tools, as a means against the late complications of diabetes, anti-cancer, anti fibromya diseases such as pulmonary fibrosis, fibrosis of the liver or kidney fibrosis, hypertrophy and hyperplasia of the authorities, especially when hyperplasia or hypertrophy of the prostate.

Compounds according to the invention are very effective inhibitors of the cellular sodium-proton-antinomies (PA+/N+exchanger), which in numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.,) also increased in these cells, which are easily accessible to measurements, such as, for example, in erythrocytes, platelets or leukocytes. Therefore, the compounds according to the invention is used as an excellent and simple scientific tools, for example, in their application as diagnostic tools for the detection and differentiation of certain forms of hypertension, as well as the proactive therapy to prevent the Genesis of high blood pressure, for example, essential hypertension.

In addition, it was found that the compounds of formula I have a favorable effect on lipoproteins of serum. As you know, for the occurrence of atherosclerotic changes in blood vessels, especially coronary heart disease, too high fat blood, the so-called hyperlipoproteinemias, represent a significant risk factor. Therefore, for the prevention and regression of atherosclerotic plaques attach exceptional importance to reduce high amounts of serum lipoproteins. Along with the decrease in the total serum cholesterol attach special importance to reduce the number of specific atherogenic lipid fractions that total cholesterol, especially low density lipoprotein (LDL) and very low density lipoproteins (VLDL), as these lipid fractions are atherogenic risk factor. On the contrary, high-density lipoprotein attributed a protective role against coronary heart disease. In line with this, hypolipidemia should be able to reduce not only the total cholesterol, but especially VLDL and LDL-fraction of serum cholesterol. Then it was found that the compounds of formula I pokayev significantly reduce elevated serum concentration of LDL and VLDL, as can be observed, for example, as a result of increased dietary intake rich in cholesterol and lipids food or with pathological changes in metabolism, for example, genetically determined hyperlipidemia. Therefore, they can be used for the prevention and regression of atherosclerotic changes, and they exclude a causal risk factor. This referred not only the primary hyperlipidemia, but also some secondary hyperlipidemia, such as occurs when diabetes. In addition, the compounds of formula I result in a certain reduction caused by abnormalities of the metabolism of heart attacks and particularly to a considerable reduction caused by the extent of infarction and its severity. Further, the compounds of formula I leads to effective protection against damage to the endothelium caused by abnormalities of metabolism. With this protection of the vessels against the syndrome of endothelial dysfunction of the compounds of formula I are valuable medicines to prevent and to treat spasms of the coronary vessels, atherogenesis and atherosclerosis, hypertrophy of the left ventricle and dilated cardiomyopathy, and thrombotic diseases.

These compounds are therefore benefits is opractice of atherogenesis; to obtain medicine for the prevention and treatment of atherosclerosis, to get medicine for the prevention and treatment of diseases, which are caused by increased levels of cholesterol, to get medicine for the prevention and treatment of diseases caused by endothelial dysfunction, to get medicine for the prevention and treatment caused by atherosclerosis, hypertension, to get medicine for the prevention and treatment caused by atherosclerosis, thrombosis, to get medicine for the prevention and treatment of hypercholesterolemia and endothelial dysfunction caused by ischemia and postischemic reperfusion damage, to get medicine for the prevention and treatment-induced hypercholesterolemia and endothelial dysfunction of cardiac hypertrophy and cardiomyopathy to obtain medicine for the prevention and treatment-induced hypercholesterolemia and endothelial dysfunction spasms of the coronary vessels and myocarditic heart attacks, to get medicine for the treatment of the mentioned diseases, in combination with lower blood pressure substances, preferably with angiotensin converting-enzyme (ACE) inhibitors and angiotensin-receptor antagonists, in combination NHMG-CoA-reductase (for example, lovastatin or pravastatin), the latter causes the hypolipidemic action and as a result increases the hypolipidemic properties of the NHE inhibitor of the formula I, is a favorable combination with intensified action and reduced use of active substances.

Declared reception of inhibitors of the metabolism of sodium-proton of the formula I as new types of drugs to lower lipid levels in the blood, and the combination of inhibitors of the metabolism of sodium-proton together with blood pressure-lowering and/or gipolipidemiceski existing drugs.

While medicines that contain compound I, can be applied orally, parenterally, intravenously or via inhalation, and the preferred application depends on the appropriate clinical picture of the disease. Thus the compounds I can be used alone or together with galenovye drugs, namely both in veterinary and in human medicine.

What excipients suitable for the desired recipe medicines, specialist known on the basis of his knowledge. Along with solvents, geleobrazovanie, the basics of candles, vspomogatel, dispersing agents, emulsifiers, defoamers, substances, corrective unpleasant taste of drugs, preservatives, agents, dissolution or dyes.

For oral use, the active compounds are mixed with appropriate additives, such as substances-carriers, stabilizers or inert diluents, and conventional methods result in suitable forms of administration, such as tablets, coated tablets, capsules, aqueous, alcoholic or oily solutions. As inert carriers can be used, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. This form of manufacturing medicines can be as dry granulation and wet granulation. As oily substances carriers or solvents take into account, for example, vegetable and animal oils, such as sunflower oil or cod-liver oil.

For subcutaneous or intravenous administration, the active compounds, if necessary, with the usual substances, such as agents of dissolution, emulsifiers or other auxiliaries, lead in the form of a solution, suspension or emulsion. As R is an example, ethanol, propanol, glycerin, along with them also sugar solutions such as glucose or mannitol, or a mixture of various of the aforementioned solvents.

As a pharmaceutical composition for the destination in the form of sprays or sprinklers are suitable, for example, solutions, suspensions or emulsions of the active substances of the formula I in a pharmaceutically not calling fears solvent, especially ethanol or water, or in mixtures of such solvents.

The composition as needed may also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, as well as working gas. This dosage form contains an active ingredient generally in a concentration of from about 0.1 to 10, especially from about 0.3 to 3 wt.%.

The prescribed dosage of the active substance of the formula I and frequency assignments depend on the effectiveness and duration of the applied compounds; in addition, on the type and severity of the disease, which is treated, sex, age, weight and individual susceptibility of a mammal that is being treated.

On average, the daily dose of the compounds of formula I sustain 1 mg/kg of body weight. In acute outbreaks, approximately immediately after the transfer of myocardial infarction may also be necessary even higher and especially more frequent dosing, for example, up to 4 doses per day. In particular, for intravenous use, as for example in a patient with infarction in the intensive care unit may require doses up to 200 mg per day.

List of abbreviations:

Meon - methanol,

DMF - N,N-dimethylformamide,

RT - room temperature,

HER - ethyl acetate (EtOAc),

Smp - melting point

THF is tetrahydrofuran,

eq. - equivalent.

Experimental part

General instructions for receiving benzoylpyridine (I)

Option a: from benzoic acids (II, L=OH)

1.0 equivalent of a derivative of benzoic acid of formula II is dissolved or suspended in anhydrous THF (5 ml/mmol) and then stirred with 1.1 equivalent of carbonyldiimidazole. After stirring for more than 2 h at RT in the reaction solution is injected 5.0 equivalents of guanidine. After stirring over night distilled THF under reduced pressure (rotary evaporator apparatus), mixed with water, set pH 6-7 using 2 N. Hcl and filtered corresponding to the tion, methanol or ethereal hydrochloric acid or other pharmacologically tolerated acids into the corresponding salt.

General instructions for obtaining benzoyl-guanidine (I).

Option b: from complex alilovic esters of benzoic acids (II, L=O-alkyl).

1.0 equivalent complex Olkiluoto ester of benzoic acid of formula II and 5.0 equivalents of guanidine (free base) are dissolved in isopropanol or suspended in THF and to complete metamorphosis (monitoring by thin-layer chromatography) is heated to boiling (typical reaction time is 2-5 hours). The solvent is distilled under reduced pressure (rotary evaporator apparatus), absorb IT and washed 3 times with a solution Panso3. Dried over Na2SO4the solvent is distilled off in vacuum and chromatographic on silica gel with a suitable solvent, for example, HER/Meon 5:1. (Formation of salt cf. a).

Example 1: 4-atomic charges-2-chloro-5 - trifluoromethyl-benzylguanine hydrochloride: colorless crystals M++N=324 of 2-chloro-4-hydroxy - 5-trifluoromethyl-benzylguanine by acetylation using acetylchloride in the presence of cesium carbonate in NMP and the subsequent formation of the hydrochloride option A.

Prize 4-hydroxy-2-methoxy-5-trifluoromethyl-benzylguanine by acetylation using acetylchloride in the presence of cesium carbonate in NMP and the subsequent formation of the hydrochloride option A.

Example 3: 3-atomic charges-2-methoxy-5-tert. -butyl-benzylguanine hydrochloride: colorless crystals M++N=308 of 3-hydroxy-2-methoxy-5-tert.-butyl benzylguanine by acetylation using acetylchloride in the presence of cesium carbonate in NMP and the subsequent formation of hydrochloride for option A.

1. Orthotamine benzoylpyridine formula I

< / BR>
where R(1) - H, alkyl with 1-8 C-atoms, or Xa-(CH2)b-(CF2)c-CF3where a, b, C=0;

one of the two substituents R(2) and R(3) means-O-CO-R(27) where R(27) - alkyl with 1-8 C-atoms, and the other of the substituents R(2) or R(3) is defined as R(1);

R(4) is hydrogen, alkoxy with 1-4 C-atoms, F, Cl, Br, I;

R(5) is hydrogen,

and their pharmaceutically tolerated salts.

2. Orthotamine benzoylpyridine formula I on p. 1, where R(1) - H, alkyl with 1-8 C-atoms, or Xa-(CF2)c-CF3where a, C=0, one of the two substituents R(2) and R(3) means-O-CO-R(27) where R(27) - alkyl with 1-4 C-atoms, and the other of the substituents R(2) or R(3) is defined as R(1); R(4) is hydrogen, alkoxy with 1 or 2 C-atoms, F, Cl; R(5) is hydrogen.

3. Orthotamine benzoylpyridine under item 1 or 2 of formula I, where R(1) - H, alkyl with 1-4 C-atoms or Xa-CF3th of the substituents R(2) or R(3) is defined as R(1); R(4) - methoxy, F, Cl; R(5) is hydrogen.

4. Orthotamine benzylguanine on PP.1-3 of the formula I, where R(1) - H, alkyl with 1-4 C-atoms or CF3one of the two substituents R(2) and R(3) means-O-CO-CH3and the other of the substituents R(2) or R(3) is defined as R(1); R(4) - methoxy, F, Cl; R(5) is hydrogen.

5. Orthotamine benzoylpyridine formula 1 according to one of paragraphs.1-4, inhibiting Na+/H+exchange.

6. Orthotamine benzoylpyridine formula 1 according to one of paragraphs.1-4 to obtain medicine for the treatment and prevention caused by coronary artery disease States.

7. Orthotamine benzoylpyridine formula 1 according to one of paragraphs.1-4 to obtain medicine for the treatment and prevention of heart attacks and arrhythmias.

8. Orthotamine benzylguanine on PP.1-4 to obtain medicine for the treatment and prevention of angina.

9. Orthotamine benzylguanine on PP.1-4 to obtain medication for treatment and prophylaxis of ischemic conditions of the heart.

10. Orthotamine benzylguanine on PP.1-4 to obtain medication for treatment and prophylaxis of ischemic conditions of the peripheral and Central nervous system and stroke.

state of the peripheral organs and limbs.

12. Orthotamine benzylguanine on PP.1-4 to obtain medication for the treatment of States of shock.

13. Orthotamine benzylguanine on PP.1-4 to obtain the drug for use in surgery and transplant organs.

14. Orthotamine benzylguanine on PP.1-4 to obtain medicine for preservation and storage of transplants for surgical purposes.

15. Orthotamine benzylguanine on PP.1-4 to obtain medication for the treatment of diseases in which cell proliferation represents a primary or secondary cause, such as protivoateroskleroticheskim tool, the tool against late diabetic complications, cancer, fibromya diseases such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidney, prostatic hyperplasia.

16. Orthotamine benzylguanine on PP.1-4 to obtain medicine for the treatment and prevention of disorders of lipid metabolism.

17. Drug, possess inhibitory activity against Na+/H+exchange, including active substance and target additional additives, characterized in that as the asset is

 

Same patents:

The invention relates to novel ortho-substituted benzoylpyridine formula (1), where R(1) denotes H, halogen, Xand-(CH2)b-(CF2)with-CF3, a, b, C denote the zero, one of the two substituents R(2) and R(3) denotes hydroxyl, and the other of the substituents R(2) and R(3) is R(1), R(4) denotes a1-C4-alkyl, halogen, (CH2)n-(CF2)o-CF3n, mean zero, and their pharmaceutically acceptable salts

The invention relates to substituted guanidines thiophenemethylamine acid of the formula I

< / BR>
where mean:

at least one of the substituents R(1), R(2) and R(3)

- Op-(CH2)s-CqF2q+1, R(40)CO - or R(31)SOk-;

p is zero or 1;

s is zero, 1, 2, 3 or 4;

q 1,2, 3,4, 5, 6, 7 or 8;

k is zero, 1 or 2;

R(40) alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms,

cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF, methyl or methoxy;

R(31) alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl or methoxy;

or

R(31) NR(41)R(42);

R(41)and R(42)

independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms,

perfluoroalkyl with 1, 2, 3 or 4 C-atoms,

or

R(41)and R(42)

together 4 or 5 methylene groups, of which CH2-group may be replaced by oxygen, S, NH, N-CH3or N-benzyl;

and sootwetstwii-OgaWITHraH2raR(10);

PA zero or 1;

mA zero, 1, 2, 3, 4, 5, 6, 7 or 8;

ga zero or 1;

ha zero, 1, 2, 3 or 4;

R(10) cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl, where the phenyl is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl and methoxy;

R(4) and R(5)

independently from each other hydrogen, F, Cl, Br, I, CN, alkyl with 1, 2, 3, 4, 5, 6,

7 or 8 C-atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(14)R(15);

R(14)R(15)

independently from each other H, alkyl with 1, 2, 3 or 4 C-atoms or perfluoroalkyl of 1, 2, 3 or 4 C-atoms

and their pharmaceutically tolerable salts

The invention relates to phenylselenenyl guanidium alkenylboronic acid of the formula (I)

< / BR>
where T means

< / BR>
moreover, R(A) denotes hydrogen, fluorine, chlorine, bromine, iodine, CN, IT, OR(6), (C1-C4)-alkyl, Or(CH2)aCbF2b+l, (C3-C8-cycloalkyl or NR(7)R(8); where

r denotes zero or 1;

a represents zero, 1, 2, 3 or 4;

b means 1, 2, 3 or 4;

R(6) means (C1-C4)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C6)-alkenyl, (C3-C8-cycloalkyl, phenyl or benzyl;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR(9)R(10);

where

R(9) and R(10) mean hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(7) and R(8) independently of one another are specified for R(6) the value, or

R(7) and R(8) together mean 4 or 5 methylene groups, of which one CH2group can be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(B) R(C) and R(D) independently from each other are specified for R(A) mn is od CN, OR(12), (C1-C8)-alkyl, Op(CH2)fCgF2g+l, (C3-C8-cycloalkyl or (C1-C9)heteroaryl;

R denotes zero or 1;

f is zero, 1, 2, 3 or 4;

g means 1, 2, 3, 4, 5, 6, 7 or 8;

R(12) means (C1-C8)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8)-alkenyl, (C3-C8-cycloalkyl, phenyl or benzyl,

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR(13)R(14); where

R(13) and R(14) denote hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(E) has independently specified for R(F) value;

R(1) independently has a specified T value; or

R(1) means hydrogen, -OkCmH2m+l, -On(CH2)pCqF2q+1, fluorine, chlorine, bromine, iodine, CN, -(C= O)-N=C(NH2)2, -SOrR(17), -SOr2NR(31)R(32), -Ou(CH2)vWITH6H5, -Ou2-(C1-C9-heteroaryl or-Su2-(C1-C9-heteroaryl;

k is zero or 1;

m means zero, 1, 2, 3, 4, 5, 6, 7 or 8;

n denotes zero or 1;

p denotes zero, 1, 2, 3 or 4;

q is 1, 2,with hydrogen, (C1-C8)-alkyl or (C1-C8)-perfluoroalkyl or

R(31) R(32) together form a 4 or 5 methylene groups, of which one CH2group can be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(17) implies (C1-C8)-alkyl;

u means zero or 1;

u2 means zero or 1;

v means zero, 1, 2, 3 or 4;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup, -(CH2)wNR(21)R(22), NR(18)R(19) and (C1-C9)-heteroaryl;

where

R(18) R(19), R(21) R(22) independently of one another denote (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

w is 1, 2, 3 or 4;

moreover, a heterocycle (C1-C9)-heteroaryl not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl or metoxygroup;

R(2), R(3), R(4) and R(5) independently of one another are specified for R(1); or

R(1) and R(2) or R(2) and R(3) together mean a group-CH-CH=CH-CH-, which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl, metoxygroup, -(CH2)w2NR(24)R(25) and NR(26)R(27);

where
is 1, 2, 3, or 4;

and the molecule contains at least two residue is T, at most three;

and their pharmaceutically acceptable salts

The invention relates to orthotamine benzoylpyridine formula (1), where R(1) denotes R(13)-SOmm denotes the number 2; R(13) denotes alkyl, one of the substituents R(2) and R(3) represents hydrogen; and the other CHR(30)R(31), R(30) represents-(CH2)g-(CHOH)h-(CH2)I-(CHOH)k-R(32), R(32) denotes hydrogen or methyl, g, h, I is equal to zero, k is 1, R(2) and R(3) represents-C(OH)R(33)R(34), R(31), R(33) R(34) denote hydrogen or alkyl, R(4) denotes alkyl, alkoxy, F, Cl, Br, I

The invention relates to compounds of formula (I), where R1, R3-R8 means XYaWZ or X YaWZ', where X Is O; Y - alkylene with 1 to 4 atoms of CH2= 0 , and W is CH2or, if W does not follow directly behind the heteroatom group HUandalso About; Z is-C(=O)R(15) or, if W does not mean Oh, also NR(16)R(17); R(15) is-N=C(NH2)2R(16) and R(17) is hydrogen or alkyl or R(16) and R(17) imply together 4 or 5 methylene groups, of which one CH2-group may be replaced by oxygen or N-(p-chlorophenyl); X' is-C(=O)NR(30); Z' is-C(= O)R(15), N-containing heterocycle with 1-5 C-atoms, and N-containing heterocycle linked through C; the other of R1, R3-R8, which do not fall under the above values, independently of one another denote VpQqU, where V - O, p=0 or 1, q=0, U is hydrogen, alkyl, and one of the substituents R5-R8 are not hydrogen

The invention relates to andinorganic formula I, a method for obtaining medicinal product based on it

The invention relates to new derivatives of 1-afterheading formula (I)

where R2, R3, R4, R5, R6, R7, R8 denote H, F, CL, Br, I, CF3XaYbZ, X stands for O, a=0,1, Y means alkylene, and one of the CH2 groups may be replaced by O-phenylene, b=zero or 1, Z denotes H, alkyl,/=O/ R/15, NR/16/ R/17/ or phenyl, which may be unsubstituted or substituted, or Z means a nitrogen-containing heterocycle with 1-5 carbon atoms, and their pharmaceutically acceptable salts

The invention relates to medicine, namely to homeopathic, treatment and prevention tools for internal and external use, has tonic, anti-inflammatory, wound healing, detoxifying, anti-microbial, antianginal, anti-atherosclerotic, antioxidant, antihypoxic, neuroprotective, sedative, cardioprotective, anti-arrhythmic, angioprotective, stress-protective, immunotropic, antifungal, nephroprotective, hepatoprotective, gastroprotective, thermoprotector, lipoic, megaproducer, radioprotective, and retinoprotective anticoordination action

The invention relates to the field of medicine and relates to an infusion solution for improving cerebral circulation

The invention relates to novel ortho-substituted benzoylpyridine formula (1), where R(1) denotes H, halogen, Xand-(CH2)b-(CF2)with-CF3, a, b, C denote the zero, one of the two substituents R(2) and R(3) denotes hydroxyl, and the other of the substituents R(2) and R(3) is R(1), R(4) denotes a1-C4-alkyl, halogen, (CH2)n-(CF2)o-CF3n, mean zero, and their pharmaceutically acceptable salts
The invention relates to medicine, namely to intensive cardiology, and for the treatment of myocardial infarction

The invention relates to the field of medicine

The invention relates to medicine, namely to surgery, and can be used in coronary artery bypass surgery for the treatment of patients with ischemic heart disease and other heart operations with long-term cross-clamping of the aorta

The invention relates to biotechnology, genetic engineering, medicine and can be used to treat coronary artery disease

The invention relates to medicine, namely to the use of compounds of the number benzofuroxan as a means for treating angina
Up!